Lawrence Robbins, M.D.
NOTE: This is a shortened version of an article published in the March issue of Practical Pain Management (available online).
Migraine is a relatively common illness, affecting 12% of the population. Chronic migraine (CM) is a frequently encountered subset of migraine, and presents certain difficulties in treatment. Those with CM have at least 15 headache days per month, with at least 8 days being migrainous in nature. In addition, medication overuse headache cannot be a major contributing factor to the headache pattern. Many with CM do not do well with the usual preventive approaches, and suffer from refractory chronic migraine (RCM). Patients with RCM have failed on at least 3 types of preventive medications. A number of our usual migraine preventive approaches have limited efficacy, and side effects often limit use. Additionally, effectiveness often diminishes over time. New preventive approaches are needed for chronic migraineurs.
Calcitonin gene-related peptide (CGRP) is an important neuropeptide involved in the migraine process. CGRP receptors are ubiquitous in the sites that are involved in migraine pathogenesis. CGRP is involved in mast cell degranulation, neurogenic inflammation, and the subsequent vasodilation. During a migraine, CGRP levels usually rise. For those with migraine, infusions of CGRP may precipitate an attack. During a migraine, trigeminal nerves that are activated may release CGRP, as well as other inflammatory compounds. The monoclonal antibodies (mAbs) that inhibit CGRP have been effective for a number of patients with chronic migraine.
Our current oral migraine preventives include antidepressants, anticonvulsants, and medications used for hypertension. These have limited efficacy, and often are not tolerated. Onabotulinumtoxin A is more effective than the oral preventives, and has few side effects. For those with chronic migraine, there is a need for more effective preventives. The CGRP monoclonal antibodies that may help to fill that role.
Erenumab-aooe (referred to as erenumab in this article), was the first CGRP mAb to become commercially available, in May of 2018. Erenumab is a subcutaneously administered once-per-month injection. There are currently 2 other mAbs available: fremanezumab and galcanezumab. These are all large molecule mAbs, with little penetration through the blood brain barrier. Erenumab targets the CGRP receptor, while the others in this class affect the CGRP ligand. These large molecule mAbs have several major advantages, including little or no drug interactions. In addition, they are cleared through the reticuloendothelial system, and do not irritate the liver or kidneys. Demand for these newer preventives has been brisk, as there has been a paucity of effective therapies for those with chronic migraine.
We evaluated the results of erenumab after the first 6 months of treatment. The first study involved 220 consecutive chronic migraine (CM)patients, after 3 months of therapy. 43% of all patients experienced 0 to 30% relief. 34% reported 30 to 70% relief, while 24% described 70 to 100% relief. Among the 43% with only 0 to 30% relief, many did choose to continue with erenumab. Many of these patients did state that they were satisfied with 15 to 30% relief. Forty-eight patients dropped off of the erenumab after months 1 or 2. Ten percent of patients reported almost complete (95 to 100%) relief over the 3 months. The patients in this study were relatively more refractory than those in the Phase 3 erenumab studies. These patients had all utilized at least 3 preventives, and almost all had tried onabotulinumtoxin A. One hundred thirty-two of the patients were considered to have refractory chronic migraine. In this study, the efficacy of erenumab was reasonable, even considering the relatively refractory population. We do not know how efficacy will hold up over time.
There were a considerable number of side effects reported by the 220 patients. Constipation was the most prevalent, at 20%. The constipation was severe in some patients, requiring treatment. At least 4 patients discontinued the erenumab primarily due to constipation. Nausea (7%) was also described, as was an increased headache (5%). The nausea usually resolved, but with an increase in headaches, the erenumab was usually discontinued. Fatigue (5%) was sometimes severe, requiring discontinuation of the medication. Joint pain (3%) sometimes accompanied the severe fatigue.
Depression (3%) was sometimes exacerbated after erenumab was started. Anxiety (2%) also occurred was described. Diarrhea was seen in 2% of patients, and several patients experienced severe diarrhea. Injection site reactions (2%) were mild, not requiring discontinuation.
We observed 3 serious side effects. One 21-year-old had a probable migraine-related stroke. Her cognitive symptoms have improved, but she is left with mild to moderate dysgraphia. She had a history of hemiplegic migraine (although none for 3 years), and had been using erenumab for 4 months. She was also on a low dose birth control pill that contained estrogen. The second patient is a 31-year-old with severe neurologic symptoms, which began 2 weeks after her 2nd erenumab injection. She also suffered from severe fatigue, with joint pains. Symptoms did eventually resolve (but they recurred 3 months later, off of the medication). The third patient suffered severe fatigue and joint pain 3 weeks after receiving the erenumab. She had a history of rheumatoid arthritis, which had been in remission. She eventually improved with corticosteroid therapy. The erenumab was probably a factor in these serious side effects. Serious side effects are a major concern with these CGRP monoclonal antibodies.
The second study evaluated 26 poor responders (0 to 15% relief) versus 26 patients with an excellent outcome (70 to 100% relief). Both of these groups consisted of relatively refractory patients, with a history of headaches that averaged 28 years. The location of headaches for both groups was primarily both anterior and posterior. Sixteen of the 26 in the poor response group reported neck pain, and 10 in the excellent group. Central sensitization syndromes were more commonly encountered in the excellent group (11 vs. 5 patients). Most patients suffered from anxiety. Depression (15 in the poor group, 17 in the excellent group) was frequently encountered, although less than anxiety. Insomnia was commonly encountered as well. Sixteen of the poor response group was considered to have refractory chronic migraine, while only 7 in the excellent group had been diagnosed with RCM. The poor response group was more likely to have moderate (6 vs. 2) or severe refractory chronic migraine (6 vs. 1) than in the excellent response group. This author has published on separating RCM into mild, moderate, and severe. We used a 10-point scale to determine the level of refractoriness. It may be clinically useful to separate refractory patients into these different levels. All of these patients had tried onabotulinumtoxin A therapy. Eight of the poor group had responded well, while 12 in the excellent group did well with onabotulinumtoxin A. A number of the patients continued with onabotulinumtoxin A, along with the erenumab. The majority of patients had a positive response to triptans. In the poor response group, 18 had good responses to opioids, while only 8 of the excellent group responded to opioids. A number of the patients had responded well to butalbital compounds (12 and 10 patients).
The third study evaluated those 50 patients who had completed 6 months of therapy. The average relief started with 36% and 35% for the initial 2 months, but slowly declined to 27% by the end of the 6th month. Patients who averaged 0 to 15% relief for the first 2 months were assessed. They continued to do poorly, with 13/15 patients experiencing 0% to 15% after 6 months. Only one patient improved significantly over time. Similarly, most of the patients(N=9) who did very well (70% to 100% relief) for the first 2 months generally continued to have success. After 6 months, 6 of these 9 patients maintained the excellent relief.
The 2 main issues with CGRP mAbs for migraine prevention are: 1. will these remain reasonably effective over time, and 2. what is the true side effect profile. The efficacy question will only be answered after several more years of treatment. Regarding side effects, this author has major concerns about the various risks that could arise due to blocking of CGRP on a chronic basis. The following are some concerns.
CGRP most likely is an inhibitor of platelet aggregation. Blocking this effect may increase the chance for cardiac or cerebrovascular effects. As of Sept. 30th, 2018, there were at least 6 cerebrovascular events listed on the FDA site. This author has put in a Freedom of Information Request for details on those events. This author has heard about several other erenumab-related strokes, yet to be officially reported, in addition to the one reported in this study.
CGRP plays some role in the prevention of hypertension, and may be somewhat protective for cardiovascular disease. CGRP is a powerful vasodilator, particularly in the meningeal and cerebral arteries. Blocking CGRP may lead, under certain circumstances, to intracerebral vasoconstriction. It is possible that other related compounds, such as amylin or adrenomedullin, may help compensate for the loss of CGRP. In addition, various vasodilators may also help to mitigate negative effects from CGRP antagonism. These include nitrous oxide, vasoactive intestinal peptide, and others. CGRP also is important in neovascularization. CGRP enhances recovery from ischemia by stimulating angiogenesis. CGRP helps to prevent secondary lymph edema, and enhances lymphangiogenesis. The adverse health consequences on the above systems, by blocking CGRP, are unknown.
The effects of CGRP mAbs on hormones has not been studied. The hypothalamus and pituitary are not, for the most part, protected by the blood brain barrier (BBB). CGRP is present in these areas. In theory, CGRP antagonism could result in various hormonal effects. The choroid plexus, involved in CSF production, also is not protected by the BBB. In addition, the area postrema, involved in nausea and vomiting, is not protected by the BBB. Circumventricular organs, important in homeostasis of various functions, are also not protected. Studies have yet to be done regarding the effects of CGRP mAbs on these areas.
CGRP is involved with skin blushing, flushing, cold sensitivity, itch, edema, and thermoregulation. After surgery, or after a serious burn, healing may be impaired by the CGRP mAbs. CGRP does play a role in the metabolism of bone, and is involved with bone healing. In diabetics, by antagonizing CGRP, there may be a higher risk for coronary artery disease. In the GI tract, CGRP has myriad functions. CGRP is involved in motility, and in protecting the gastric mucosa. Constipation may occur with CGRP antagonism, and to a lesser degree, diarrhea. None of the above effects have been studied, with regard to the CGRP mAbs.
We do not want to use these medications during pregnancy. There may be more risk to the CGRP mAbs in later stages of pregnancy. Preliminary studies in animals have not revealed major issues with the newborn animal.
A number of patients have reported severe fatigue from erenumab. Additionally, joint pain has been an issue for some patients. It is possible that the hypothalamic-pituitary-adrenal (HPA) axis may be involved with these side effects, as the HPA axis is not protected by the BBB. There have been no studies of CGRP mAbs and the HPA axis.
As of December 31, 2018, 7300+ possible side effects had been reported to the FDA; over 800 were deemed serious. Only a fraction of side effects are officially reported to the FDA. It is very concerning that we have a paucity of studies on the serious consequences of blocking CGRP for long periods of time.
Until we know more, it is prudent to screen patients for risk. Informed consent should be obtained. Patients at increased risk may include those with risk factors for stroke, including the usual risk factors (lipids, HTN, diabetes, family history, cigarettes). In addition, at higher risk may be patients with clotting abnormalities, positive lupus anticoagulant, or positive anticardiolipin antibodies. It is possible that hemiplegic migraine, or those with frequent auras, may represent an increased risk as well. Certain birth control pills may be a problem, although this is controversial. Patients with recent surgery, or who have suffered a recent fractured bone, should possibly delay the use of the CGRP mAbs. Those with active GI ulcers, or with inflammatory disease of the GI tract, may also be at an increased risk. Because of the possible hypothalamic and pituitary effects, patients with various hormonal issues may be affected. The effects on bone growth, as well as on hormones, cautions against using these treatments in children and adolescents. We need studies in all of these areas.
There are major limitations to this study. It is retrospective, and studies #2 and #3 had limited numbers of patients. The patients are relatively refractory, as compared to most migraineurs. We relied on diaries and calendars, as well as patients’ self-reported histories. These are not always accurate. Most, but not all, of the patients maintained calendars of their migraine days. We were not able to ascertain whether each of the reported side effects was due to the erenumab. This is basically an observational study, with no control group.
The major strength of this study is that the patients were not selected for any purpose other than migraine treatment. They represented a “real life” group of migraineurs, albeit relatively refractory. We also were able to tease out and complete an analysis of poor responders vs. excellent responders. The 6- month results may be helpful in understanding efficacy over longer periods of time.
References/ For Further Reading
- Lassen LH, Haderslev PA, et al. CGRP may play a causative role in migraine. Cephalalgia 2002; 22:54-61
- Tepper, S. Anti-Calcitonin Gene-Related Peptide (CGRP) Therapies: Update on a previous review after the American Headache Society 60th Scientific Meeting, San Francisco, June 2018. Headache 2018; 58:276-290
- Reuter U. Anti-CGRP antibodies: a new approach to migraine prevention. Lancet Neurol. 2014; 13(9):857-859
- Tepper SJ, Ashina M, Reuter U, et al. Safety and efficacy of erenumab for preventive treatment of chronic migraine: A randomized, double-blind, placebo-controlled phase 2 trial. Lancet Neurol 2017; 16: 425-434.
- Goadsby PJ, Reuter, U, et al. A controlled trial of erenumab for episodic migraine N Engl J Med 2017; 377:2123-2132
- Dodick DW, Ashina M, et al. ARISE: A Phase 3 randomized trial of erenumab for episodic migraine. Cephalalgia 2018; January https://doi.org/10.1177/0333102418759786(Epub ( ahead of print)
- Reuter U, Goadsby PJ, et al. Efficacy and safety of erenumab in episodic migraine patients with 2-4 prior preventive treatment failures: Results from the Phase 3b LIBERTY study. Emerging science platform presentation and poster 009. American Academy of Neurology meeting, Los Angeles, April 24, 2018(abstract).
- Depre C, Antalik L, et al. A randomized, double-blind, placebo-controlled study to evaluate the effect of erenumab on exercise time during a treadmill test in patients with stable angina. PO-01-198. Cephalalgia 2017; 37(Supplement 1):340-341.
- Tepper SJ, Pascual J, et al. Analysis of blood pressure following short-term and long-term treatment with erenumab. Poster 105. 68th American Academy of Neurology meeting, Los Angeles, CA, April 25, 2018(abstract)
- Headache classification committee of the international headache society (HIS). The international classification of headache disorders, 3rd edition (beta version). Cephalalgia 2013.
- Refractory chronic migraine: a consensus statement on clinical definition from the European Headache Federation. J Headache Pain 2014; 15:47.
- American Psychiatric Association (2013). Diagnostic and statistical manual of mental disorders (5th edition), Washington, D.C.
- Robbins, L Refractory chronic migraine: long-term follow-up using a refractory rating scale. J Headache Pain 2012; 13:225-229.
- Matsumato Y, Ueda S, et al. CGRP inhibits human platelet aggregation. Japan Circulation J 1996;60(10):797-804.
- FDA Medwatch adverse drug site: fda.gov/safety/medwatch (erenumab aooe).
- Russell, FA, King, R et al. Calcitonin Gene-Related Peptide: physiology and pathophysiology Physiol Rev 2014;94:1099-1142.
- Majima, M, Ito, Y, et al. CGRP/CGRP receptor antibodies: potential adverse effects due to blockade of neovascularization Trends in Pharmacological Sciences 2018 (e published) https://doi.org/10.1016/j.tips.2018.11.003
- Brain S, Grant A Vascular actions of Calcitonin Gene-Related Peptide and Adrenomedullin Physiol Rev 2004;84:903-934
- Deen M, Correnti E, Kamm K, et al. Blocking CGRP in migraine patients-a review of pros and cons. J Headache and Pain 2017;18(1):96.
- Gangula PR, Zhao, et al. Pregnancy and steroid hormones enhance the vasodilation responses to CGRP in rats. Am J of Physiol Heart Circ Physiol 1999;276:H284-H288.